Apparatus for the nasal or oral delivery of a medicament

ABSTRACT

An apparatus ( 1 ) for the nasal or oral delivery of a medicament, comprises: (a) a sealed flexible container ( 3 ) containing the medicament and a gaseous propellant for the medicament; and (b) a delivery device ( 5 ), comprising: (i) a main body part ( 5   a ) which, at least in use, holds the sealed flexible container ( 3 ); and (ii) a compressive part ( 5   b ) which, when actuated in use, causes the sealed flexible container ( 3 ) to be ruptured and the propellant to expel the medicament from the container, thereby delivering the medicament.

RELATED APPLICATIONS

This application is a 35 U.S.C. 371 national stage filing ofInternational Application No. PCT/GB02/04487, filed 3 Oct. 2002, whichclaims priority to Great Britain Patent Application No. 0123959.9 filedon 5 Oct. 2001 in Great Britain. The contents of the aforementionedapplications are hereby incorporated by reference.

The present invention relates to the nasal or oral delivery ofmedicaments, and in particular to an apparatus therefor, for example anasal or oral inhaler.

According to a first aspect, the present invention provides an apparatusfor the nasal or oral delivery of a medicament, comprising:

-   (a) a sealed flexible container containing the medicament and a    gaseous propellant for the medicament; and-   (b) a delivery device, comprising:    -   (i) a main body part which, at least in use, holds the sealed        flexible container; and    -   (ii) a compressive part which, when actuated in use, causes the        sealed flexible container to be ruptured and the propellant to        expel the medicament from the containers thereby delivering the        medicament.

A second aspect of the invention provides a delivery device for thenasal or oral delivery of a medicament, comprising:

-   -   (i) a main body part arranged to hold, in use, a sealed flexible        container containing a medicament and a gaseous propellant for        the medicament; and    -   (iii) a compressive part arranged to cause, when actuated in        use, a sealed flexible container held by the main body part to        be ruptured and the propellant to expel the medicament from the        container, thereby delivering the medicament.

Preferably the delivery device of the second aspect of the inventioncomprises the delivery device of the apparatus of the first aspect ofthe invention. Consequently, once the sealed flexible containercontaining a medicament and a gaseous propellant is installed in thedelivery device according to the second aspect of the invention, theapparatus according to the first aspect of the invention is provided.

The invention has the advantage that it generally provides a simple(both in terms of use and in terms of manufacturability) yet reliableway of delivering a pre-determined dose of a medicament into the nose ormouth of a patient.

Examples of possible therapeutic uses for the invention include:treatments for addictions (e.g. smoking, cocaine or other addictivedrugs, obesity, etc.); pharmaceuticals affected by “first pass”metabolism in the gut; female hormones and/or osteoporosis; HIV/AIDS;migraine and/or acute pain; respiratory diseases and/or allergies;vaccines and/or treatment of infectious diseases.

The compressive part of the delivery device preferably comprises a partwhich is movable with respect to the main body part so as to compressthe sealed flexible container. Actuation of the compressive partpreferably therefore comprises movement of the compressive part withrespect to the main body part such that the sealed flexible container iscompressed. Advantageously, such movement of the compressive part may beachieved by depressing, preferably manually, the compressive part withrespect to the main body part. Additionally or alternatively, theactuation of the compressive part may comprise the compressive partsliding with respect to the main body part, for example.

In preferred embodiments of the invention, the compressive part ishinged or otherwise rotatably mounted with respect to the main body partof the delivery device. Advantageously, the compressive part may behinged to the main body part by means of a flexible web (preferably apolymeric web) commonly known as a “living hinge”.

The main body part of the delivery device preferably comprises a holdingpart and a nozzle. The holding part is arranged to retain the sealedflexible container which contains the medicament and the propellant, andthe nozzle is arranged to guide the expelled medicament into the nose ormouth (as required) of the patient during use. The holding partpreferably includes retaining means to retain the sealed flexiblecontainer in place. For example, the holding part may include one ormore recesses or the like for receiving and retaining an edge portion ofthe sealed flexible container.

The compressive part and the main body part of the delivery devicepreferably include interlockable members such that when the compressivepart is depressed, rupturing the sealed flexible container, thecompressive part interlocks with the holding part. Preferably suchinterlocking prevents further depression of the compressive part, forexample thereby preventing the compressive part interfering with thedelivery of medicament to the patient. Additionally or alternatively,such interlocking of the compressive part with the holding part mayprevent a second actuation of the apparatus, thereby making theapparatus a single use apparatus. In this way, the patient is preventedfrom attempting to re-use the apparatus once the medicament has beendelivered, thereby preventing the patient from inadvertently re-usingthe apparatus and believing that he has received a dose of medicamentwhen in fact he has not. Advantageously, the apparatus may include avisible indication of when the apparatus has been actuated—for example asuitably coloured portion on the compressive part and/or the holdingpart—which is visible only once the apparatus has been actuated.

The sealed flexible container preferably is installed in the deliverydevice prior to its supply to the patient, and this is preferablyachieved by the delivery device being openable by means of the abovementioned hinge or other rotatable mounting of the compressive part withthe holding part. Once the sealed flexible container has been installedin the delivery device, the delivery device preferably is closed aroundthe container. Advantageously, the closing of the delivery device may beachieved by means of interlockable members of the main body part and thecompressive part; preferably these are the same interlockable memberswhich interlock when the apparatus is actuated. Most preferably, themain body part and the compressive part of the delivery device includeinterlockable members which are arranged to undergo a two-stageinterlocking action. The first interlocking action preferably closes thedelivery device, for example around the sealed flexible containerinstalled in the device. The second interlocking action preferablyoccurs upon actuation of the apparatus. As mentioned above, once thesecond interlocking action has occurred, an indicator (e.g. a colouredindicator) preferably is visible, indicating that the apparatus has beenactuated and cannot (or should not) be re-actuated.

Preferably once the apparatus has been actuated and the medicament hasbeen delivered to the patient, the device is closed in such a way thatit cannot easily be reopened, thereby substantially preventing theremoval of the flexible container. The apparatus may be closed by meansof the above-mentioned interlockable members of the compressive part andthe holding part of the delivery device, for example.

The delivery device is preferably formed from a polymer material, forexample a polyolefin (e.g. polyethylene and/or polypropylene) or apolyacrylate (e.g. polymethylmethacrylate). The delivery device ispreferably moulded, for example injection moulded or blow moulded. Thedevice is preferably moulded as a single integral part.

The sealed flexible container is preferably formed from metal foiland/or flexible polymeric sheet material. Most preferably the containeris formed from a laminate of one or more layers of metal foil andpolymeric sheet material, e.g. a laminate of aluminium foil andpolyethylene sheet. The container is preferably heat sealed. As analternative to a laminated container it may be made from a single hingedmoulded part or two separate moulded parts to be sealed at the fillingstage, for example. Preferably the container provides a barrier to airand micro-organisms and prevents leakage of the medicament, anyexcipients or propellant.

Advantageously the flexible container may include a frangible portionwhich is designed to rupture when the container. (containing the gaseouspropellant and the medicament) is compressed, in use, by the compressivepart. The frangible portion preferably takes the form of one or morelines of weakness along which the container is designed to break when socompressed; such lines of weakness may have the form of an arc or a starshape, for example. The frangible portion is arranged such that when thesealed container is installed in the delivery device it is locatedadjacent to the nozzle of the device, thereby facilitating delivery ofthe medicament to the patient.

An alternative (or an addition) to the weakness lines on the leadingedge of the medicament pouch (i.e. the flexible container) is amodification to the body of the device. A rear-facing protrusionadjacent to the noble (e.g. an annular protrusion) may be required, e.g.to assist in the release of medicament from some types of laminates orplastics used for forming the pouch. The actuation pressure from theuser's thumb on the top of the device will depress the top surface ofthe pouch and drive it forward onto the annular protrusion. This willlead to the pouch bursting at this point to facilitate the release ofmedicament through the front of the pouch and onwards into the delivery“tunnel” to the nasal cavity. The annular protrusion may also act as asealing feature, preventing loss of contents and pressure, for example.

For the atomisation of some liquids to be delivered it may be necessaryto include within (or adjacent to) the “tunnel” of the nozzle a baffle,sieve, mesh insert, or other atomising means.

The gaseous propellant contained in the sealed flexible container may beat a pressure above atmospheric pressure (i.e. pressurized) prior to thecompression of the flexible container by the compressive part of thedelivery device (i.e. the gaseous propellant may be pressurized assupplied in the flexible container). Alternatively, the gaseouspropellant may be substantially at (or even below) atmospheric pressureas supplied, and pressurized only upon compression of the flexiblecontainer by the compressive part of the device.

Examples of suitable propellants contained within the container include:air, oxygen, nitrogen, argon, or substantially any non-CFC propellantsuitable for human inhalation. The medicament may be in powder and/orliquid and/or vaporous and/or gaseous form; for example it may beinhaled in the form of a spray and/or a powder.

The invention will now be described, by way of example with reference tothe accompanying drawings, of which:

FIG. 1 shows an embodiment of the apparatus according to the invention,in cross-section, prior to delivery of its medicament;

FIG. 2 shows, in cross-section, the embodiment of FIG. 1 during deliveryof the medicament;

FIG. 3 (views (a) to (c)) shows, schematically, the assembly and use ofthe apparatus of FIGS. 1 and 2;

FIG. 4 (views (a) to (d)) shows, schematically, a further embodiment ofthe apparatus according to the invention;

FIG. 5 (views (a) and (b)) shows another embodiment of the apparatusprior to delivery of its medicament; and

FIG. 6 (views (a) and (b)) shows the embodiment of the apparatus shownin FIG. 5, during delivery of the medicament.

FIG. 1 shows an apparatus 1 for the nasal or oral delivery of amedicament, comprising a sealed flexible container 3 containing themedicament and a gaseous propellant for the medicament, and a deliverydevice 5. The delivery device 5, which is moulded from polymer material,comprises a main body part 5 a which, at least in use, holds the sealedflexible container 3, and a compressive part 5 b which, when actuated inuse, causes the sealed flexible container 3 to be ruptured and thepropellant to expel the medicament from the container, therebydelivering the medicament. The sealed flexible container 3 is a heatsealed laminate of aluminium foil and polyethylene, heat sealedflat-edges of which are retained in a recess 7 of the main body part 5 aof the delivery device 5. The container contains pressurized propellantgas and a medicament in liquid or powder form. The container includes afrangible portion 9 in the form of a line of weakness which is designedto rupture when the container is compressed sufficiently.

The delivery device 5 includes a pair of opposed finger grips 11, one onthe compressive part 5 b and the other on the main body part 5 a. Thedelivery device also includes an integrally moulded flexible web 13 at arear end of the device which acts as a “living hinge”, and at theopposite, front, end of the device there is a nozzle 15 by which themedicament is delivered to a patient. (The nozzle 15 as shown is fornasal use; it would generally be modified for oral inhalation.) In use,the patent grips the apparatus between the thumb and one or more fingersof the same hand and squeezes the compressive part 5 b and the main bodypart 5 a of the delivery device together (i.e. the compressive part isdepressed with respect to the main body part). This actuation of thedevice compresses the sealed flexible container 3 between thecompressive part 5 b and the main body part 5 a, thereby pressurizingthe propellant gas within the container. The pressure of the propellantgas upon the frangible portion 9 of the container causes the frangibleportion to rupture, as indicated by reference numeral 17 in FIG. 2,thereby releasing the propellant gas and the medicament 19 contained inthe container, both of which are expelled from the apparatus via thenozzle 15 (as indicated by the arrow in FIG. 2). In this way themedicament is delivered to the nose or throat of the patient.

A front portion 21 of the compressive part 5 b and an adjacent portion23 of the main body part 5 a comprise interlockable portions. Theinterlockable portions 21 and 23 are arranged to undergo a two-stageinterlocking action. The first interlocking stage occurs when thedelivery device 5 is closed around the sealed flexible container 3, oncethe container is installed in the device in the assembly plant. Theapparatus 1 therefore is supplied to the end-user with the deliverydevice 5 closed by means of the interlockable portions 21 and 23 intheir first interlocking stage—as shown in FIG. 1, i.e. with portion 21of the compressive part interlocked with surface 23 a of portion 23.When the compressive part 5 b is actuated in use, by being depressedwith respect to the main body part 5 a, the interlockable portions 21and 23 undergo their second interlocking stage—as shown in FIG. 2, i.e.with portion 21 of the compressive part interlocked with surface 23 b ofportion 23.

Upper facing surface 21 a of portion 21 is provided with a coloured,indicator mark (e.g. a red indicator strip) which is not visible in thefirst interlocking stage but is visible once the apparatus has beenused, i.e. in the second interlocking stage. In this way the patient isprovided with a visible means of indication that the apparatus has beenused and cannot be used again. A shoulder 25 on the main body partprevents over depression of the compressive part 5 b (which couldotherwise block the nozzle 15 hindering the delivery of the medicament).

FIG. 3( a) is a schematic view illustrating the installation of thesealed flexible container 3 in the form of a “blister pack” in thedelivery device 5 of the apparatus shown in FIGS. 1 and 2. FIG. 3( b)shows the apparatus with the container 3 installed; theinterlockable-portions 21 and 23 have interlocked in the first of theirtwo-stage interlocking action. FIG. 3( c) shows a patient using theapparatus to deliver a medicament nasally. It can be seen from FIGS. 3(a) and 3(b) that in this embodiment of the invention the compressivepart 5 b is recessed within the main body part 5 a of the apparatus.This diminishes the possibility of inadvertent actuation duringpackaging or transportation, for example.

FIG. 4 shows another embodiment of the apparatus 1 according to theinvention, in which the compressive part 5 b is larger than that of theembodiment shown in the preceding figures. FIG. 4( a) is a side viewshowing the main body part 5 a and the compressive part 5 b of thedelivery device fully opened to allow the insertion of a sealed flexiblecontainer 3 (not shown) containing the medicament and propellant, intothe apparatus 1. The main body part 5 a includes the nozzle 15 fordelivering the medicament. A recess 7 for retaining a heat-sealed flatedge of the flexible container is shown, as are interlockable portions21 and 23 of the delivery device, portion 23 being an aperture in whichthe projection 21 is receivable. The delivery device is opened by meansof a flexible polymeric web 13 which functions as a living hinge.

FIG. 4( b) shows the delivery device being actuated by the compressivepart 5 b being depressed with respect to the main body part 5 a, asindicated by arrow A. In this embodiment of the invention, the deliverydevice is partially open prior to actuation (i.e. the two stageinterlocking action described above is not present in this embodiment).The depression of the compressive part 5 b with respect to the main bodypart 5 a compresses the sealed flexible container (not shown) which hasbeen inserted into the delivery device. The compression of the sealedflexible container causes the container to rupture, and causes thepropellant in the container to expel the medicament from the container,thereby delivering the medicament to the patient via the nozzle 15, asindicated by arrow B.

FIG. 4( c) shows a detail of the interlockable portions 21 and 23 priorto their interlocking during actuation of the apparatus 1 as shown inFIG. 3( b). The portion 21 includes a coloured indication mark 25 (e.g.a red mark) which is visible through the aperture 23 when thecompressive part has been fully actuated and portion 21 has interlockedwith aperture 23. This provides a visible indication that the apparatushas been used and cannot be re-used.

FIG. 4( d) shows the apparatus 1 subsequent to its actuation as shown inFIGS. 4( b) and (c). The apparatus is fully closed, i.e. the main bodypart 5 a and the compressive part 5 b of the delivery device areinterlocked with each other by means of portions 21 and 23. The fingergrip 11 of the compressive part is visible, but the finger grip of themain body part is depressed.

FIG. 5( a) shows a plan view, and FIG. 5( b) shows a cross-sectionalside view, of another embodiment of the apparatus according to theinvention prior to the delivery of its medicament. This embodiment issimilar to the previously described embodiments, with like featuresindicated by the same reference numerals. However, this embodimentincludes a rear-facing protrusion 27 in the form of an annularprotrusion surrounding the inwardmost entry to the nozzle of thedelivery device. This protrusion assists in the rupture of the flexiblecontainer and the consequent release of the medicament and the gaseouspropellant. The protrusion also helps to provide a degree of sealingbetween the ruptured container and the nozzle, and assists the guidanceof the medicament and propellant into and through the nozzle. FIG. 6(views (a) and (b)) shows this embodiment of the invention duringdelivery of the medicament.

1. An apparatus for the nasal or oral delivery of a medicament to apatient, comprising: (a) a sealed flexible container including themedicament and a gaseous propellant for the medicament; and (b) adelivery device, including: (i) a main body part which, at least in use,holds the sealed flexible container, the main body part including anozzle by which the medicament is delivered to the patient; and (ii) acompressive part which, when actuated in use, compresses the sealedflexible container, thereby pressurizing the gaseous propellant withinthe container, which pressurization of the gaseous propellant causes tosealed flexible container to be ruptured and the propellant to expel themedicament from the apparatus, thereby delivering the medicament to thepatient; wherein the main body part includes a protrusion adjacent tothe nozzle, to assist the rupturing of the sealed flexible container,the protrusion being arranged such that the compression of the sealedflexible container by the compressive part causes the sealed flexiblecontainer to be driven against the protrusion and thereby to be rupturedwhere it meets the protrusion.
 2. The apparatus according to claim 1,wherein the sealed flexible container is formed from one of a metal foiland a polymeric sheet material.
 3. The apparatus according to claim 2,wherein the sealed flexible container comprises a laminated structureformed from a metal foil laminated to a polymeric sheet material.
 4. Theapparatus according to claim 1, wherein the sealed flexible container ismolded and comprises one or more parts.
 5. The apparatus according toclaim 1, wherein the sealed flexible container comprises a frangibleportion adapted to rupture when the compressive part of the deliverydevice is actuated in use.
 6. The apparatus according to claim 1,wherein the propellant included in the sealed flexible containercomprises one or more of air, oxygen, nitrogen, argon, and substantiallyany non-CFC propellant suitable for human inhalation.
 7. The apparatusaccording to claim 1, wherein the medicament is in one or more of apowder form, a liquid form, a vapor form, and a gaseous form.
 8. Theapparatus according to claim 1, wherein each of the compressive part andthe main body part include an interlockable member, such that when thecompressive part is actuated the compressive part interlocks with themain body part.
 9. The apparatus according to claim 8, wherein theinterlockable members are arranged to undergo a two-stage interlockingaction including a first stage and a second stage, wherein the firststage includes closure of the delivery device to hold the sealedflexible container, and wherein the second stage occurs open actuationof the compressive part.
 10. The apparatus according to claim 1, whereinthe compressive part comprises a part which is movable with respect tothe main body part so as to compress the sealed flexible container, andactuation of the compressive part includes such movement.
 11. Theapparatus according to claim 1, wherein actuation of the compressivepart is arranged to be carried out by manual depression of thecompressive part with respect to the main body part.
 12. The apparatusaccording to claim 1, wherein the compressive part is one of hinged androtatably mounted with respect to the main body part.
 13. The apparatusaccording to claim 12, wherein the compressive part is hinged to themain body part by a flexible web.
 14. The apparatus according to claim1, further comprising atomizing means, disposed in or adjacent to thenozzle, to atomize a liquid medicament.
 15. The apparatus according toclaim 1, further comprising a visible indicator for indicating when theapparatus has been activated.
 16. The apparatus according to claim 15,wherein the visible indicator comprises a colored portion disposed onone of the compressive part and the main body part.
 17. The apparatusaccording to claim 1, wherein the protrusion is an annular protrusionsurrounding any entry to the nozzle.
 18. A delivery device for the nasalor oral delivery of a medicament, comprising: (i) a main body partarranged to hold, in use, a sealed flexible container containing amedicament and a gaseous propellant for the medicament the main bodypart including a nozzle by which the medicament is delivered to thepatient; and (ii) a compressive part arranged to cause, when actuated inuse, a sealed flexible container held by the main body part to beruptured and the propellant to expel the medicament from the container,thereby delivering the medicament, wherein each of the compressive partand the main body part include an interlockable member by which thecompressive part may interlock with the main body part, wherein theinterlockable members are arranged to undergo a two-stage interlockingaction including a first stage and a second stage, wherein the firststage includes closure of the delivery device to hold the sealedflexible container, and wherein the second stage occurs upon actuationof the compressive part; and wherein the main body part includes aprotrusion adjacent to the nozzle, to assist the rupturing of the sealedflexible container, the protrusion being arranged such that thecompression of the sealed flexible container by the compressive partcauses the sealed flexible container to be driven against the protrusionand thereby to be ruptured where it meets the protrusion.
 19. The deviceaccording to claim 18, wherein the compressive part comprises a partwhich is movable with respect to the main body part so as to compressthe sealed flexible container, and actuation of the compressive partcomprises such movement.
 20. The or device according to claim 18,wherein actuation of the compressive part is arranged to be carried outby manual depression of the compressive part with respect to the mainbodypart.
 21. The device according to claim 18, wherein the compressivepart is one of hinged and rotatably mounted with respect to the mainbody part.
 22. The device according to claim 21, wherein the compressivepart is hinged to the main body part by a flexible web.
 23. The deviceaccording to claim 18, in which the main body part comprises a nozzle bywhich the medicament is delivered, in use.
 24. The device according toclaim 23, wherein the main body part comprises a protrusion, adjacent tothe nozzle, to assist the rupture of the flexible container.
 25. Thedevice according to claim 23, further comprising atomizing means,disposed in or adjacent to the nozzle, to atomize a liquid medicament.26. The device according to claim 18, wherein the interlocking of theinterlockable members prevents re-actuation of the compressive part. 27.The device according to claim 18, wherein, when the compressive part hasbeen actuated, the compressive part interlocks with the main body partsuch that further depression of the compressive part is substantiallyprevented.
 28. The device according to claim 18 further comprising avisible indicator for indicating when the device has been actuated,which is visible only once the apparatus has been actuated.
 29. Thedevice according to claim 28, wherein to visible indicator comprises acolored portion disposed on one of the compressive part and the mainbody part.
 30. The device according to claim 18, wherein the deliverydevice is formed from a polymer material.
 31. The device according toclaim 30, in which the delivery device is molded as a single integralpart.
 32. The device according to claim 18, wherein the gaseouspropellant contained in the sealed flexible container is in apressurized state prior to actuation of the compressive part.
 33. Thedevice according to claim 18, wherein the gaseous propellant ispressurized only upon actuation of the compressive part.
 34. Theapparatus according to claim 18, wherein the protrusion is an annularprotrusion surrounding an entry to the nozzle.